In a number of inflammatory diseases, including rheumatoid arthritis (RA) and dermatitis, there is excessive and inappropriate complement activation as well as an excessive concentration of IL-1 in the plasma.
Complement system is part of the innate immune system, acting to protect the host from microorganisms such as bacteria, and other foreign and abnormal cells (e.g. apoptotic cells). However, primarily protective, complement activation can also cause damage to the host. C5, the fifth component of the complement system is a glycoprotein consisting of 1679 amino acids in two disulfide-linked polypeptide chains, C5α and C5β (2). After activation by the C5 convertase, which is activated by immune complexes (IC), C5 is cleaved into C5a and C5b. C5a, displays powerful biological activities that lead to inflammation (1) (3). It is a strong chemoattractant involved in the recruitment of inflammatory cells such as neutrophils, eosinophils, monocytes, and T lymphocytes, the activation of phagocytic cells and the induction of the release of granule-based enzymes and generation of oxidants, all mechanisms that may contribute to innate immune functions but also tissue damage. Excessive complement activation leading to elevated plasma levels of C5a is known to be associated with many clinical conditions, including sepsis, adult respiratory distress syndrome, rheumatoid arthritis, Alzheimer's disease (4), and ischemic heart disease.
C5b, on the other hand, through its multiple binding sites, initiates and directs the assembly of the membrane attack complex (MAC). C5b serves as an anchor for the assembly of C6, C7, C8, and C9 (known as C5b-9) and is inserted into the cell membrane of the pathogens, leading to cell lysis.
There is therefore a need for a medicament which is able to specifically target C5a and not C5b. An anti-05 monoclonal antibody had been developed for being used in therapy. This antibody prevents collagen-induced arthritis and ameliorates established disease (5) (6). However, this antibody blocks both C5a and C5b, the decrease of C5b levels which is necessary for formation of MAC is a drawback of this antibody.
There is therefore still a need for a more specific therapy only targeting C5a and letting C5b intact. As demonstrated herein, an oligonucleotide-based therapy is assumed to be specifically targeting C5a while keeping the C5b intact for formation of MAC.
The pro-inflammatory cytokine interleukin-1 (IL-1) is an important mediator controlling local and systemic effects on a wide variety of target cells, there by regulating immunity and inflammation (7). It mediates inflammation by recruitment of neutrophils, activation of macrophages and stimulation of T and B cells.
IL-1 binds to IL-1 receptor type I (IL-1RI), which results in the recruitment of the IL-1 receptor accessory protein (IL-1RAcP) (8). IL-1RAcP does not recognize the ligand but stabilizes IL-1 binding to the IL-1RI. Furthermore, IL-1RAcP is a crucial co-receptor in this complex by enabling recruitment and binding of intracellular adaptor proteins such as MyD88 and kinases such as IL-1R-associated kinases, ultimately leading to NF-κB activation. In addition to the trans-membrane form of IL-1RAcP, a smaller and soluble protein comprising the three extracellular Ig domains and a unique C-terminal domain has been identified. This sIL-1RAcP is mainly produced by the liver (29) and circulates systemically. Another member of IL-1 receptor family is IL-1RII which upon binding of IL-1 also associates with IL-1RAcP; however, this doesn't lead to signal transduction. So this receptor is considered as a decoy receptor and can be found in trans-membrane and soluble forms (9).
IL-1 levels increase in some inflammatory diseases like rheumatoid arthritis. So it is necessary to decrease and regulate the level and the activity of IL-1. sIL-1RAcP can interact with soluble IL-1RII thus forming a high affinity IL-1 scavenger (8) and it has been already shown (9) that systemic over-expression of sIL-1RAcP by an adenoviral expression vector in mice markedly ameliorates collagen-induced arthritis (CIA). Therefore there is a need for a medicament for increasing the amount of circulating sIL-1RAcP. Adenoviral over-expression of sIL-1RAcP is not attractive since virus vectors may be considered as unsafe and are not easy to generate. As demonstrated herein, an oligonucleotide-based therapy is thought to be more specific, safer and cheaper than such virus-based therapy.
Several treatments are already known to treat an inflammatory disease such as RA. However, each of these treatments has drawbacks. Therefore there is still a need for designing new treatments for inflammatory diseases such as RA which do not have all the drawbacks of existing treatments.